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dc.contributor.authorZhang, Jing
dc.contributor.authorQin, Yaowu
dc.contributor.authorMartinez, Mireya
dc.contributor.authorFlores-Bellver, Miguel
dc.contributor.authorRodrigues, Murilo
dc.contributor.authorDinabandhu, Aumreetam
dc.contributor.authorCao, Xuan
dc.contributor.authorDeshpande, Monika
dc.contributor.authorQin, Yu
dc.contributor.authorAparicio-Domingo, Silvia
dc.contributor.authorRui, Yuan
dc.contributor.authorTzeng, Stephany Y
dc.contributor.authorSalman, Shaima
dc.contributor.authorYuan, Jin
dc.contributor.authorScott, Adrienne W
dc.contributor.authorGreen, Jordan J
dc.contributor.authorCanto-Soler, M Valeria
dc.contributor.authorSemenza, Gregg L
dc.contributor.authorMontaner, Silvia
dc.contributor.authorSodhi, Akrit
dc.date.accessioned2021-06-17T13:08:30Z
dc.date.available2021-06-17T13:08:30Z
dc.date.issued2021-06-15
dc.identifier.urihttp://hdl.handle.net/10713/16037
dc.description.abstractTherapies targeting VEGF have proven only modestly effective for the treatment of proliferative sickle cell retinopathy (PSR), the leading cause of blindness in patients with sickle cell disease. Here, we shift our attention upstream from the genes that promote retinal neovascularization (NV) to the transcription factors that regulate their expression. We demonstrated increased expression of HIF-1α and HIF-2α in the ischemic inner retina of PSR eyes. Although both HIFs participated in promoting VEGF expression by hypoxic retinal Müller cells, HIF-1 alone was sufficient to promote retinal NV in mice, suggesting that therapies targeting only HIF-2 would not be adequate to prevent PSR. Nonetheless, administration of a HIF-2-specific inhibitor currently in clinical trials (PT2385) inhibited NV in the oxygen-induced retinopathy (OIR) mouse model. To unravel these discordant observations, we examined the expression of HIFs in OIR mice and demonstrated rapid but transient accumulation of HIF-1α but delayed and sustained accumulation of HIF-2α; simultaneous expression of HIF-1α and HIF-2α was not observed. Staggered HIF expression was corroborated in hypoxic adult mouse retinal explants but not in human retinal organoids, suggesting that this phenomenon may be unique to mice. Using pharmacological inhibition or an in vivo nanoparticle-mediated RNAi approach, we demonstrated that inhibiting either HIF was effective for preventing NV in OIR mice. Collectively, these results explain why inhibition of either HIF-1α or HIF-2α is equally effective for preventing retinal NV in mice but suggest that therapies targeting both HIFs will be necessary to prevent NV in patients with PSR.en_US
dc.description.urihttps://doi.org/10.1172/JCI139202en_US
dc.language.isoenen_US
dc.publisherAmerican Society for Clinical Investigationen_US
dc.relation.ispartofJournal of Clinical Investigationen_US
dc.subjectAngiogenesisen_US
dc.subjectHypoxiaen_US
dc.subjectMouse modelsen_US
dc.subjectOphthalmologyen_US
dc.subjectRetinopathyen_US
dc.titleHIF-1α and HIF-2α redundantly promote retinal neovascularization in patients with ischemic retinal diseaseen_US
dc.typeArticleen_US
dc.identifier.doi10.1172/JCI139202
dc.identifier.pmid34128478
dc.source.volume131
dc.source.issue12
dc.source.countryUnited States


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